DESCRIPTION (Applicant's abstract): Prison diseases encompass a heterogeneous group of transmissible and spontaneous disorders. Altered forms of the prison protein (PrP) appear to play a central role in their pathogenesis. In this transmissible prison disorders, a protease-resistant form termed PrPSC accumulates in the brain and appears to be a component of the agent of the disease. However, in the generic prison disorders, PrPSC is often not detected. Instead, new data suggests that a transmembrane form of PrP (termed ctmPrP) is involved in triggering neurodegeneration in genetic prison diseases, and that a protective factor in brain normally prevents ctmPrP expression. The applicant proposes to establish a defined framework, using transgenic mice and derived cell lines, to study the role of both ctmPrP and host genes with which it interacts. The applicant will test the hypotheses that ctmPrP is involved at an early step in the pathway of cellular pathology of all prison diseases, and that transmission of disease and neuronal cell death are independent features of prison disorders. The applicant will attempt to develop new biochemical assays for the molecular mechanisms involved in one or more of the classical features of selected prison diseases, such as incubation time, and the nature, extent and location of neurodegeneration. Through this work, a novel paradigm of prison disease pathogenesis will be established and specific hypotheses on the role of host genes that influence ctmPrP will be tested. The proposed studies set the stage for the future manipulation of host factors in ways that may protect cells from prison disease.